In 2006, an HIV-positive man was diagnosed with leukemia. First he received chemotherapy, and when the cancer returned his doctor recommended a stem-cell transplant with tissues obtained from a bone-marrow donor. After finding an unusually high number of compatible donors, his doctor, Gero Hütter, had a simple idea that would change the course of HIV research. Dr. Hütter knew of a rare genetic mutation that confers immunity to many strains of HIV, including the strain that infected his cancer patient. And new blood cells, including immune cells, are manufactured by bone marrow. What if he could find a bone-marrow donor with this mutation? What effect would it have on the HIV infection?

Five years after his cancer diagnosis, the man, known as the Berlin patient and recently identified as Timothy Ray Brown, is in remission from cancer … and the most sensitive tests have been unable to detect HIV anywhere in his body, despite the discontinuation of antiretroviral drugs. Scientists are a cautious lot, careful not to make grand statements without qualifying them with words like “seem” and “suggest.” But more and more, researchers are starting to say that Brown could be the first case in which a cure for HIV was attained.

Human immunodeficiency virus, or HIV, has been the focus of intense research since the 1980s, when it was identified as the causative agent of AIDS. Many anti-HIV drugs have been developed since then, though worldwide, less than a third of people who need the drugs have access to them. Those with access, however, have significantly improved health outcomes and longer life expectancy.

But despite these critical advances, thus far, prevention remains the best strategy. HIV is trickier than most realize, and attempts to develop a vaccine or cure are confounded by the virus’ extremely fast rate of mutation and the existence of multiple strains. Because HIV, unlike many other viruses, lacks the capability to “proofread” copies of its genetic code, it is probably able to mutate many times daily within just one individual – and during the final stages of an HIV infection, a patient could have tens of millions of variants of the original viruses with which he or she was initially infected. Two HIVs in the same cell can exchange genetic material, which is another method by which novel HIV varieties arise. Furthermore, because HIV attacks the immune system itself, it is overwhelming the very elements that are necessary to destroy it. A cure for existing HIV infections would need to overcome the virus’ ability to evade immune response by hiding throughout the patient’s body, either as pieces of genetic material integrated with the host’s DNA, or as latent virus particles hiding out in immune cells.

Until recently, the idea of a cure for HIV infection was widely regarded with pessimism in the scientific community. But Timothy Ray Brown’s successful bone-marrow transfusion has in turn given HIV research scientists a transfusion of optimism – talk of a cure is once again on the table, and it’s possible that even if a cure is not immediately found, superior treatments might soon replace antiretroviral drug cocktails.

This illustration shows how HIV uses a co-receptor, such as CCR5, to gain entry into a host cell. Image: National Institute of Allergy and Infectious Diseases

HIV works by interlocking with receptors on the surface of immune cells called helper T cells; this physical interaction allows the virus entry. Many strains of HIV attach to a co-receptor called CCR5. Interestingly, about 1 percent of people of European descent have a genetic mutation that results in helper T cells that lack the CCR5 co-receptor, and are naturally resistant to infection by the strains of HIV that require CCR5 to infect cells. (Other strains of HIV can use a different co-receptor to enter cells.)

In 2009, Dr. Hütter and colleagues reported in the New England Journal of Medicine that the bone-marrow transfusions resulted in undetectable levels of HIV in the patient’s body. A 2010 follow-up in Blood confirmed that 45 months after the transplants, Brown had a normal T-cell count and that his own T-cells had been wiped out and replaced by HIV-resistant donor-derived cells. While positive proof can’t be attained without analyzing every cell in Brown’s body, the authors’ assessment, that “it is reasonable to conclude that cure of HIV infection has been achieved in this patient,” is about as optimistic a statement as can be made in the normally tentative language of scientific journals.

Unfortunately, this procedure isn’t practical for the millions of people with HIV worldwide. The operation is fatal to about one in three patients; in Brown’s case, the procedure was medically justified as a treatment for leukemia. His immune system had to be wiped out with chemicals and radiation before receiving the bone-marrow transplant. In addition to the high risk of the procedure, finding matching bone-marrow donors with the mutated CCR5 gene is no easy task.

This treatment does, however, provide a proof of concept for the idea that HIV can be treated with gene therapy – a procedure that, in theory, can replace a patient’s gene with a more desirable version of that gene. Gene therapy for HIV could replace a functional gene – the one that codes for the CCR5 receptor – with a nonfunctional gene – the one that does not code for a CCR5 receptor. Perhaps such mutant CCR5 genes could be genetically engineered into a patient’s own cells, bypassing the need to find a matching donor.

The theoretical underpinnings of gene therapy are rock solid, but in the past there have been problems getting it to work in actual cells. In a late 1990s study, for example, CD34+ umbilical-cord-blood cells were engineered with genes that would interfere with HIV’s ability to express its own genes. The vector used to insert the genes into the blood cells killed the very blood cells it was supposed to protect – and this was just one of many problems faced by the researchers. When engineering cells, researchers must use a selectable marker gene, which is a piece of DNA that confers certain physical characteristics (usually antibiotic resistance) onto the transformed cells. This makes it readily apparent that the insertion of the other bits of foreign DNA, such as those conferring resistance to HIV infection, was successful. The marker gene itself can be problematic and has the potential, if expressed, to cause a severe, perhaps lethal, allergic reaction when inserted into the human genome.

Secondly, engineered genes insert themselves randomly into the genome, which could have a deleterious effect. For instance, in humans they might be inserted adjacent to and induce expression of a gene that could lead to uncontrolled cell division and possibly cancer. Controlling where in the genome a desired gene inserts itself is another important goal for those interested in gene therapy. Problems such as these lessened interest in gene therapy as a treatment for HIV infection in the years prior to Dr. Hütter’s apparent success. In a review of the literature published in 2005, it was stated that “gene therapy for AIDS does not have the potential to cure AIDS” – the consensus at the time.

Scientific consensus can change, however, and the case of the Berlin patient reenergized research into a cure – or at least superior treatments – for HIV infection. Attempts to disable the CCR5 receptor may employ the techniques of gene therapy – and in September promising preliminary results were reported from researchers who took patients’ own T-cells and removed their CCR5 receptors with an enzyme called “zinc fingers nuclease,” which targets the gene that codes for the CCR5 receptor and induces just enough of a mutation to result in a nonfunctioning gene. The enzyme is removed before the cells are returned to the patients’ bodies, and the method itself avoids some of gene therapy’s previous pitfalls – no marker genes, no random insertion. The experiment only used 15 tests subjects, but they experienced a relatively high proportion of resistant T-cells that endured for about six months, a result that might help researchers home in on more effective treatments for HIV at the genetic level.

Although HIV research has yielded many failures in the search for vaccines and cures, each failure has in turn produced new insights into how the virus functions, giving scientists more leads to follow. Even if these leads culminate in dead ends, the work scientists do to get there is important. And finally, for the first time in years, scientists now seem to be cautiously optimistic about an eventual cure for HIV, and the belief that their grueling efforts will someday pay dividends is what drives researchers to continue their work.

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